1. Field
The subject invention relates to the field of vitamin D precursors, such as (3aR,4S,7aS)4-bromooctahydro-7a-methyl-1H-indene-1,5-dione, and in particular to a process for producing such derivatives.
2. Description
The compound (3aR,4S,7aS)4-bromooctahydro-7a-methyl-1H-indene-1,5-dione (the compound of formula II, below) is a key intermediate in the preparation of the vitamin D analogs. The preparation of this compound was originally reported by Daniewski, A. R. and Kiegiel, J., J. Org. Chem., 53: 5534 (1988). The synthesis involved stereoselective 1,4-reduction of the ketone of formula I (see below) in the presence of 38 mol % of tert-butylcopper(I) catalyst (P3) and subsequent bromination of the resulting enolate [Daniewski, A. R. and Kiegiel, J., Synth. Commun., 18: 115 (1988)]. The compound of formula II was isolated in a yield of 57% after purification by silica gel chromatography and crystallization. However, the tert-butylcopper catalyst is unstable, making this procedure was difficult to reproduce and mandating precise temperature control. ##STR2##
It is known that reducing the ketone of formula I produces the trans-hydrindan derivative of formula 5, the carbon skeleton of which, although quite common in the structure of many natural products, including vitamin D and steroids, is difficult to synthesize since thermodynamically the corresponding cis-isomer (such as, the compound of formula 6) is strongly favored. ##STR3##
The reduction of the compound of formula I with diisobutylaluminum hydride ("DIBALH") in the presence of MeCu as a catalyst (P1) was hardly satisfactory, giving a 4:3:3 mixture of the compounds of formulas 5, 6, and 7, respectively. Thus, the stereo- and the regioselectivity were only 55% (the ratio of the compounds of formulas 5 to 6 was 4:3) and 70% [the ratio of the compounds of formulas 5 plus 6 to 7 was 7:3], respectively. Stereoselectivity increased to 66% is with n-butylcopper (catalyst P2) and to 90% with tert-butylcopper catalyst. However, regioselectivity remained virtually unchanged and the compound of formula 7 was isolated typically in 30% yield. Accordingly, the isolated yield of the desired bromo-ketone of formula II never exceeds 57% after the reaction is quenched with bromine, even though a high stereoselectivity (90%) has been achieved with the tert-butylcopper (catalyst P3).
TABLE 1 Stereo- and Regioselectivites in the Reduction of Ketone (I) using known catalysts. ##STR4##
Moreover, the thermal instability of tert-butylcopper due to its tendency to undergo .beta.-elimination to form isobutylene and copper hydride made this reaction difficult to reproduce since the copper hydride thus formed catalyzes a non-stereoselective 1,4-reduction. Accordingly, there was a need in the art for a superior catalyst to carry out this reaction.